The impact of Hepatitis C virus infection on kidney transplantation outcomes : A systematic review of 18 observational studies

Background: Hepatitis C virus (HCV) infection occursin 0% to 51% of dialysis patients, and manyHCV-positive patients are urged to undergo kidney transplantation. However, the outcome of renal transplantation in HCV-positive recipients is unknown. Objectives: Our review aimed to address the outcomesof renal transplantation recipients (RTRs)following kidney transplantation. Materials and Methods: We selected studies that used the adjusted relative risk (aRR) and 95% CI of all-cause mortality and graft loss in HCV-positive compared with HCVnegative RTRs as study endpoints. Cox proportional hazard analysis was usedin all studies to calculate the independent effects of HCV infection on RTR outcomes. Sixteen retrospective cohort studies and 2 clinical trials were selected for our review. Sixteen studies were related to patient survival, and 12 examined graft survival. Results: The combined hazard ratio in HCV-infected recipients was 1.69-fold (1.33-1.97, p < 0.0001) and 1.56 times (1.22-2.004, p < 0.0001) greaterthan that of HCV-negative recipients for mortality and graft loss, respectively. Conclusions: Although HCV-infected RTRs have worse outcomes than HCV-negative RTRs,kidney transplantation is the preferred treatment for patients with HCV infection and end-stage renal disease. A R T I C L E I N F O Article history: Received: 26 Apr 2010 Revised: 31 Jan 2011 Accepted: 28 Feb 2011


Control and
Prevention (CDC) detects HCV infection by enzyme linked immunosorbent Implication for health policy/practice/resear

ongly recommend reading this interesting article to all general pra
titioners, surgeons, nephrologists and urologists.


Please cite this paper as:

Rostami Z, Nourbala MH, Alavian SM, Bieraghdar F, Jahani Y, Einollahi B. The impact of hepatitis C virus infection on kidney tra splantation outcome: A systematic review of 18 observational studies.Hepat Mon.2011;11(4):247-54.assay (ELISA) in 8.1% (range 0% to 51%) of ESRD patients in large dialysis centers (2).Additionally, manyHCV-positivepatients are urged to undergokidney transplantation (3).The major cause of mortality due to liver failure in kidney transplant recipients is HCV infection (4).The outcome of renal transplantation in HCV-positive recipients is unknown (2,5); some studies havereported better survival in HCV-positive ESRD pati nts compared with those remaining on dialysis (1,4, ,7).

A risein viral load following immunosuppression in

The impact of HCV on renal transplantation HCV-positive kidney transplant recipients was suggested to be a significant cause of pooroutcome (1,4,6,8).Also, viral load and liver deterioration are related (8).Conversely, several surveys did not observe worse outcomes in HCV-positive renal transplant recipients (RTRs) when HCV infection was acquired before kidney transplantation, especially during the first 5-8 years (7).However, a recent study from a US registry evaluated the effect of immunosuppressive regimens on survival in HCV-positive RTRs, demonstrating that antibody induction doesnot adversely affect patient survival (1,7,9).Moreover, cyclosporine (10) and my cophenolat mofetil (MMF) may have protective effects (1,6) and inhibit HCV replication in renal transplant patients with HCV infection.Whether hepatitis virus infected-patients should stay on dialysis or be

ferred for
idney transplantation remains unknown.


Objectives

We performed a meta-analysis to determine the

n outcomes in RT
patients.


Materials and Methods


Search strategy

We searched electronic databases, including PubMed, the Cochrane Database of Systematic Reviews, EMBASE, and CINHAL, for studies from Jan 1981 to Jan 2010 to identify those that reported the effect of HCV infection on RTR outcomes.Our keywords included "hepatitis C," "HCV infection," "kidney transplantation," "graft survival," "patients survival," "mortality," "natural history," "outcome," and their synonyms.Two authors independently developed a search strategy to identify randomized trials and cohort studies that investigated the effect of HCV on patients and graft survival after kidney transplantation.To identify additional relevant articles, reference lists from qualitative topic reviews and the identified articles were also searched.Duplicate publications were discarded.We restricted our search to human

haracteristics are summ
rized in Table 1.


Criteria for inclusion

Two independent reviewers assessed with a standard method each included trial about adult kidney transplant recipients with HCV infection, defined astesting positive for anti-HCV or HCV RNA by polymerase chain reaction (PCR) in serum at the time of enrollment.Also participants were evaluated with regard to patient and kidney outcomes, which were defined as liver-related death and return to dialysis due to HCV infection.Discrepancies were resolved in conference.Other criteria for inclusion were controlled trials and cohort studies that reported patient and graft survival among HCV-infected RTRs.Table 1 shows the characteristics of the studies in this review.Studies that included HCV-infected donors were excluded.Between the trials included in our metaanalysis, there are a few differences in patients and graft outcome (Table 2).Thus, we decided

o pool these data for evaluation.


Review
uestions and endpoints of interest

Our review aimed to answer two specific questions: 1.What is the effect of HCV nfection on renal graft survival?

2. What is the effect of HCV infe tion on renal recipient survival?

All selected studies used the adjusted relative risk (aRR) and 95% CI of all-cause mortality and graft loss in HCVpositive versus -negative RTRs as study endpoints.Cox proportional hazard 5) (we have converted HR to RR with a formula) analysis was usedin all studiesto calculate independent effects of HCV infection on RTR outcomes after adjustments for potentially contributing factors, such as age, gender, follow-up period, type of transplant, diabetes mellitus, post-transplant plasma creatinine, race, duration of dialysis, donor death etiology, and proteinuria.First-generation enzyme-linked immunoadsorbent assay test before 1991, second generation until 1997 and third generation u

il now were used to d
tect HCV


Statistical analysis

We pooled outcomes (mortality rates, renal allograft failure), which had been expressed as relative risk (RR) with 95% confidence intervals (CI), using STATA 8.The results of each outcome were analyzed for heterogeneity by Q test (the random effects method of Der Simonian-Laird).Funnel plots, Begg's rank correlation test, and Egger's regression asymmetry test were used to assess the existence of publication bias.The Forest plot was used to demonstrate the details of pooled analysis.Combined hazard ratios were asses

tivity analysis.


Results


De
cription of Included Trials

The included studies are summarized in Table 1.Follow up duration and adjusted variables for each study shown in table 2 and adjusted relative risk for mortality and gr

t loss also presented in table 3


Ef
ect on patient and graft survival

The Q-test for heterogeneity revealed p < 0.0001 (Q = 69.81,df = 15) and p < 0.0001 (Q = 66.15, df = 11) for patient and graft survival, respectively.Further, a meta-analysis was done with a random model showed a combined hazard ratio in HCV-infected recipients that was 1.69-fold (1.33-1.97,p < 0.0001) (Figure 2) and 1.56 times ( 1.22-2.004,p < 0.0001) (Figure 3) greaterthan in HCV-negative recipients for mortality an

symmetry, both of
which were non-significant [(p = 0.753, p = 0.226; Figure 4) and (p = 0.304, p = 0.55; Figure 5), respectively].Similar results were observed in the funnel plots.


Sensitivity analysis

All eligible studies included in meta-analysis.Because the elimination of each study did not have an impact on

e combined hazard rat
o, the overall estimation was robust (Figure 6).


Discussion

Hepatitis C infection is a risk factor for graft loss and death in renal transplant recipients (8).Although our report and

cent studie
have emphasized the detrimental role of hepatitis C in long-term patient and graft survival after renal transplantation (10), several studies have demonstrated that patient and graft survival on-


HR 199

The impact of HCV on renal transplantation HCV infection after renal transplantation arethe same in the shortterm compared withnon-infected renal transplant patients (6).Conversely, kidney transplantation is a better option for HCV-positive ESRD patients versus remaining on dialysis (1).To better examineHCV-positive RTR outcomes, we performed a meta-analysis using observational studies that used adjusted data of all-cause mortality.


Impact on patient survival

Consistent withFabrizi's meta-analysis, the aRR for mortality rate in our study was lower than inot

r studies (4,8,13,14,17), l
kely due to the greater sample size, early detection, improvement in management, and exact follow-up.Compared with Fabrizi's meta-analysis, which included 8 articles, our study included 18 articles that comprisedmore than 123,000 RTRs, indicatingthat greaterconsideration has been given to the controversy of HCV-infected RTR outcomes and kidney transplantation in the past5 years.Several studies have demonstrated lower patient and graft survival in HCV-positive RTRs, related in part to associated complications, such as cirrhosis, hepatocellular carcinoma, cardiovascular disease, diabetes mellitus, sepsis, higher PRA, and deceased kidney donation (1,10).


Impact on graft survival:

In our study,the aRR for graft loss was similar to that in Fabrizi's meta-analysis.Although during the

rst 5-10 years, graft and
atient survival was apparently similar between negative and positive HCV-infected RTRs (4), HCV-associated glomerulonephritis, proteinuria, and diabetic nephropathy can progressrapidly to chronic allograft nephropathy (6).


Role of other factors in mortality

It appears that the increased mortality in anti-HCVpositive patients was partially related to m

tality dueto causes other than HCV
nfection.According to a novel risk score for mortality in RTRs (29), the risk score for HCV (1.5) was not more than age above 40 years in comparison to younger than 40 (2.2-6.7),pre-transplant diabetes mellitus (1.8), post-transplant diabetes mellitus (1.5), serum creatinine levels at the first year after transplantation (1.7), and proteinuria greater than 1g during the first year of operation (2.7).In a recent meta-analysis, mortality due to liver complications, such as cirrhosis and hepatocellular carcinoma, among HCV-infected RTRs increased in most studiesthat were included, with anRRof 1.79, compared with HCV-negative recipients (6).In a systematic review, cardiovascular and infectious diseases were also important causes of death in HCV-positive RTRs (6).

Because mortality and graft loss are multifactorial, we used the aRR that had been obtained by the Cox regression model in each study to appraise the isolated influence of HCV infection on patient and graft survival.In contrast to studies that reported a negative impact, the majority of studies that demonstrated a positive impact of transplantation on HCV-infected patient and graft survival rates did not use the Cox regression model; consequently, studies that observed a positive impact or not on HCV-positive patients were excluded from this systematic review and meta-analysis.Although our study and other similar articles on the effect of HCV infection on patient and graft survival did not have any publication bias, it appears that we included only papers with a negative impact (Figure 2, 3).Consistent with previous surveys, we observed that the aRR of all-cause mortality and graft failure was significantly higher for seropositi

Role of immunosuppression in HCV-positive kidney transplant recipien
s

The progression of liver failure in HCV-positive RTRs following immunosuppression is debated.While previous studies have illustrated a detrimental effect on liver function in these patients (10,11), more recent studies have observed relatively slow development of liver fibrosis in such patients (1).Luan (2008) performed a study using national data and Cox regression analysis to estimate hazard ratios, adjusted for donor, recipient, and transplant variables.A total of 3708 HCV-positive and 75,629 HCV-negative kidney transplant recipients were included, wherein no calcineurin inhibitors (cyclosporine A or tacrolimus) or steroids had a significant impact on patient mortality.Moreover, the use of mycophenolytemofetile (MMF) not only was associated with a significantly reduction in mortality rate, it also had a protective effect (1), despite it sassociation with increased HCV viremia (1).According to another study, HCV replication increases after kidney transplantation, likely due to immunosuppression (1).In contrast, in cultured hepatocytes, cyclosporine A, but not tacrolimus, prevents HCV replication.Notably, more than 50% of HCV-positive kidney transplant recipients who are treated with cyclosporine A have stable liver function and decreased liver fibrosis (1).Nevertheless, in HCV-positive kidney transplant patients, the use of antibody induction has no correlation with viral load (1) and does not have a negative influence on patient survival in these patients (6).It appears that the anti-HCV activity of cyclosporine A differs from its immunosuppressive effects (10).Thus, based on the protective effects of new immunosuppressive drugs, such as MMF and cyclosporine, we hope for greater survival of HCV-positive renal transplant recipients.Yet, controversy still exists regarding the impact of HCV infection on the outcomes of renal transplantation.


Limit

ions

The ma
ority of articles are not complete; some did not consider Cox regression, and the aRR for patient and graft survival was not reported.Some contributing factors, such as alcohol or drug consumption, were not noted.After renal transplantation, HCV-positive patients have lower patient and graft survival rates compared with HCV-negative patients.However, HCV infection is not a contraindication for renal transplantation; and HCV therapy before transplantation is important to improve the outcome of the patients after transplantation.

Figure 1

1
Figure 1.Summary
of literature se